Nuclear hormone receptor are ligand activated transcription factors. We are
trying to understand how these receptors modulate cellular differentiation and
function and what is their contribution to diseases such as atherosclerosis
and immune response. Since the receptors transcriptional activity can
be regulated (switched on) by small lipid soluble molecules they are excellent
targets of global expression profiling.

We have been using real time quantitative PCR for absolute transcript number
determination and DNA microarrays for global transcription profiling to determine
receptor levels, target genes profiles and to identify components of the genetic
programs of receptor activation

A group of receptors such as PPARs (Peroxisome Proliferator Activated Receptor)
and LXR (Liver X Receptor) can be activated by modified fatty acids and cholesterol
molecules, respectively. Using natural and synthetic ligands we have characterized
the role of these receptors in myeloid cell differentiation, lipid metabolism
and dendritic cell differentiation.

We have found that oxidatively modified LDL (Low Density Lipoprotein) induces
and activates PPARg in monocytes leading to macrophage differentiation, expression
of the scavenger receptor CD36 and increased lipid uptake. This process operates
as a positive feed back loop and contributes to foam cell formation. PPARg also
increases lipid efflux from macrophages through induction of LXRa, a receptor
activated by oxysterols. This leads to the increased expression of the transporter
ABC1 (ATP Binding Cassette) and cholesterol efflux from macrophages. Our results
suggest the existence of a transcriptional cascade and a complex and complementary
role for PPARg and LXRa as key regulators of a coordinated cellular responses
to oxidatively modified LDL in macrophages. Recently, we have also found that
key components of this cascade also exist in maturing/differentiating antigen
presenting cells (dendritic cells) of myeloid origin. The role of these transcriptional
networks in normal cell function and diseases and their potential for therapeutic
utilization will be discussed.